The periventricular-periaqueductal gray matter (PAG) has been shown to be an important brain focus for mediating the effects of opiates on immune function. Electrical stimulation of various sites in the PAG for 20 min was found to suppress NK cell activity assessed three hours following stimulation. Eleven of 14 active sites were found to be in the caudal PAG. Most of these were located just lateral to the dorsal raphe. Stimulation of the PAG could alter NK cell activity by either activation of the HPA axis or through stimulation of peripheral sympathetic output. Intraventricular injections of the mu selective ligand (DAGO) into rat brain produced a dose-dependent suppression of NK cell activity which was antagonized by pretreatment with naltrexone. The delta selective ligand DPDPE, or the kappa receptor ligand (S, S-U50-488), had no effect on this parameter of immune function. It appears that the mu opiate receptor is involved in mediating the suppressant effects of opiates on NK cell activity.